CXC Chemokines enhance innate and adaptive immunity, regulate angiogenesis, and mediate tumor cell metastases relevant to the pathobiology of non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). CXCR3 ligands via their putative receptor, CXCR3, behave as both potent promoters of Th1 cytokine-dependent cell-mediated immunity and inhibit angiogenesis (i.e.,'immu'noangiostasis'). We hypothesize that first 'priming' the circulating pool of mononuclear cells to express CXCR3 can optimize immunoangiostasis. Second, once systemic CXCR3 levels are optimally expressed, 'induction' of intratumor CXCR3 ligand production will optimize the chemotactic gradient necessary to target circulating CXCR3+ mononuclear cells to the tumor. The combined temporal and spatial 'priming and induction' will optimize both tumor immunity and concomitant inhibition of angiogenesis. CXCR2/CXCR2 ligand biology has been determined to promote angiogenesis in a variety of solid tumors. However, mechanisms that regulate the expression of CXCR2 on human microvascular endothelial cells remain to be elucidated. We hypothesize that the CXCR2/CXCR2 ligand biology has an important role in promoting angiogenesis in cancer; and the microenvironment of the tumor regulates the expression of CXCR2 on endothelial cells that potentate their angiogenic phenotype. This postulate supports the notion that the expression of CXGR2 is, in part, under the influence of hypoxia-inducible factors (HIF), and that CXCR2 expression on tumor yasculature will correlate with tumor-associated angiogenesis and metastatic potential. The tumor microenvironment and receptor signaling within the tumor cell plays a role in promoting the expression of hypoxia-responsive genes that may be relevant in promoting tumor metastases. The CXC chemokine, CXCL12, and its receptor, CXCR4 promote metastases of a variety of solid tumors. Recent findings have linked HIF-1a and the expression of CXCR4 on tumor cells. However, the mechanism of hypoxia and/or receptor-mediated expression of CXCR4 on tumor cells have not been fully elucidated. We hypothesize that CXCR4 is a biomarker that predicts the metastatic potential of specific tumors, and that the biological axis of CXCL12/CXCR4 is a major mechanism for trafficking of tumor cells to metastatic sites. We further postulate that receptor activation of PI3kinase/PTEN/AKT/mTOR/HIF pathway in tumor cells is critical to the expression of CXCR4 and generation of a metastatic phenotype. The studies designed in this proposal will further gain insight into the role that CXC chemokines play in cancer pathobiology; and whether in preclinical animal models and in patients that modulating their biology will impact on inhibition of tumor growth, tumor- associated angiogenesis, and metastases.